Expanding the synthetic utility of enzymes

项目总结 在构建复杂性的转换中实现选择性对于能够访问目标分子至关重要 具有潜在影响人类健康的潜在药物和用于研究生物的化学探针 系统。尽管在开发用于构建复杂性的化学方法方面取得了重大进展 反应，它往往仍然是具有挑战性的高水平的化学，现场和 络合物或官能团致密分子的立体选择性。与小分子催化剂和 试剂、酶通常已经进化成具有高选择性的反应。发现了 特定的酶反应和这些催化剂的用途的开发有可能使 合成策略，并使我们能够获得具有强大生物活性的新分子。这项建议 描述了几种开发健壮的酶介导反应并利用这些工具 具有药用潜力的分子的流线型合成。 这项NIGMS提案的目标是为合成化学家提供高度选择性、高效、良好的- 特色化和可持续的生物催化方法将被规划为合成方法以实现目标 分子。利用天然产物生物合成途径和靶蛋白家族中的酶作为 首先，我们将阐明一种特定酶的天然化学功能和作用机制。由此 最初的基准，我们使用生物信息学工具、结构分析、计算建模和进化 组装对合成社区有用的互补生物催化剂面板的方法。我们 随后，寻求使用每个蛋白质类别提供的平台来设计新的反应并应用这些反应 与人类健康相关的分子的简化合成方法。我的团队正在寻找生物催化剂 反应的解决方案继续挑战现代合成化学家，包括选择性C-H 羟基化、位选择性和立体选择性氧化脱芳构化以及化学选择性和立体选择性 α-氨基酸的衍生化。展望未来，我们将继续在这些领域开展工作，并正在寻求 发展生物催化的C-C键形成反应，超越羟基化的C-H官能化反应，以及 构建和阐述诸如核苷酸的官能团致密分子的策略。 总之，这项建议描述了化学、位置和立体选择性转化的发展 由酶介导。这些方法将直接使合成具有生物活性的复杂化合物成为可能。 与人类健康相关的分子。

PROJECT SUMMARY Achieving selectivity in complexity-building transformations is critical for being able to access target molecules with potential to impact human health such has potential drugs and chemical probes for studying biological systems. Although significant strides have been made in developing chemical methods for complexity-building reactions, it often remains challenging to carry out these transformations with high levels of chem-, site- and stereoselectivity on complex or functional group dense molecules. In contrast to small molecule catalysts and reagents, enzymes often have evolved to carry out reactions with high levels of selectivity. The discovery of specific enzymatic reactions and development of the utility of these catalysts has the potential to enable to synthetic strategies and grant us access to new molecules with potent biological activity. This proposal describes several strategies for developing robust enzyme-mediated reactions and leveraging these tools for the streamlined synthesis of molecules with pharmaceutical potential. The goal of this NIGMS proposal is to provide synthetic chemists with highly selective, efficient, well- characterized and sustainable biocatalytic methods to be planned into synthetic approaches toward target molecules. Using enzymes from natural product biosynthetic pathways and targeted protein families as a starting point, we will elucidate the natural chemical function and mechanism of a given enzyme. From this initial benchmark, we use bioinformatic tools, structural analysis, computational modeling, and evolutionary approaches to assemble panels of complementary biocatalysts of utility to the synthetic community. We subsequently seek to use the platform provided by each protein class to design new reactions and apply these methods to the streamlined synthesis of molecules relevant to human health. My group seeks biocatalytic solutions to reactions that continue to challenge modern synthetic chemists including selective C–H hydroxylation, site- and stereoselective oxidative dearomatization, and the chemo- and stereoselective derivatization of a-amino acids. Moving forward, we continue to work in these areas and are seeking to develop biocatalytic C–C bond forming reactions, C–H functionalization reactions beyond hydroxylation, and strategies for building and elaborating functional group dense molecules such as nucleotides. In summary, this proposal describes the development of chemo-, site- and stereoselective transformations mediated by enzymes. These methods will directly enable the synthesis of complex biologically active molecules relevant to human health.